The goal of The Linkage and Candidate Gene Study of Nicotine Dependence is to detect, identify, and characterize genetic loci that predispose of protect individuals from the onset and persistence of nicotine dependence and that determine tobacco consumption. Heavy smoking (1 pack for 6 months or more) nicotine dependence (Fagerstrom Test for Nicotine Dependence greater than or equal to 4) affects about 10% of the population, and siblings of probands have a 40% risk of developing nicotine dependence (lambda2-3-4). 750 to 800 informative families will be recruited from HMO's (Detroit, MI; Minneapolis, N; St. Louis, MO). Roughly half of the families will be taken from the genetic epidemiology study (Project 1). Families with at least one heavy smoking nicotine dependent sibling pair will be interviewed and have their DNA sampled. Parents and other siblings who have smoked but may not be dependent will also be recruited for genetic analyses using family based association and quantitative linkage methods. A case control sample for association studies will be collected. Subjects will undergo a multi-domain assessment of cigarette use, nicotine dependence and related phenotypes. Our date set will include approximately 1200 independently counted affected sibling pairs, 800 discordant sibling samples on both parents; the remaining families are expected to have samples on one. Identify-by-state statistics that are robust to ethnic stratification can be used with these data. Candidate gene testing will be done on 950 cases and 650 controls and can be followed in 750 families using family based association tests. Two-stage genotyping using 400 markers spaced approximately 10cM will be conducted. A genomic survey will be conducted for chromosomal regions linked to nicotine dependence and related phenotypes. Sib-pair and variant component methods, quantitative and quantitative linkage analysis will be performed on the appropriate phenotypes. Areas suggestive of linkage will be followed up with additional genotyping. Candidate genes for nicotine dependence and related phenotypes will be examined. Potential candidate genes will be provided by Project 3. Bioinformatics will help guide candidate gene approaches by taking advantages of the publicly available results from human and mouse genome sequencing projects.